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Lookup NU author(s): Dr Christopher DuncanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The AuthorsIn monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells (NFKB1) in affected patients. In patients’ macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1β secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-β (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1β and/or IFN-I signaling could represent a therapeutic approach for these patients.
Author(s): Nurmi K, Silventoinen K, Keskitalo S, Rajamaki K, Kouri V-P, Kinnunen M, Jalil S, Maldonado R, Wartiovaara K, Nievas EI, Denita-Juarez SP, Duncan CJA, Kuismin O, Saarela J, Romo I, Martelius T, Parantainen J, Beklen A, Bilicka M, Matikainen S, Nordstrom DC, Kaustio M, Wartiovaara-Kautto U, Kilpivaara O, Klein C, Hauck F, Jahkola T, Hautala T, Varjosalo M, Barreto G, Seppanen MRJ, Eklund KK
Publication type: Article
Publication status: Published
Journal: Cell Reports Medicine
Year: 2024
Volume: 5
Issue: 4
Print publication date: 16/04/2024
Online publication date: 08/04/2024
Acceptance date: 18/03/2024
Date deposited: 17/04/2024
ISSN (electronic): 2666-3791
Publisher: Cell Press
URL: https://doi.org/10.1016/j.xcrm.2024.101503
DOI: 10.1016/j.xcrm.2024.101503
Data Access Statement: The original blots and cytometry histograms have been deposited to Mendeley Data and are publicly available as of the date of publication (https://doi.org/10.17632/spgdgkwbtw.1). DOI is listed in the key resources table. This publication did not generate original code or structures. Used software are listed with citations in STAR Methods. The genome sequencing data, mass spectrometry raw data, and RNA expression data is not publicly available due to the Finnish personal data protection legislation, which limits sending patient data or samples to other research centers without permission of the local Ethics Committee, and because of limitations associated to informed consent. Additional information required to reanalyze the data, including microscopy data, mass spectrometry raw data, and RNA expression data reported in this paper is available from the lead contact (kari.eklund@hus.fi) upon request. Please see the paper for the remaining data access statement
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